PROJECT SUMMARY/ABSTRACT The Drosophila midgut provides a useful model for understanding the mammalian gastrointestinal tract. Great progress has been made in associating specific configurations of our gut microbial communities with distinct physiological states. Yet, precisely how enteroendocrine cells embedded in the gut epithelium sense and signal these dynamically changing microbial cues is less well understood. Our preliminary studies have laid the foundation for a powerful new Drosophila model of the enteroendocrine system. These observations raise the central hypothesis that endocrine cells signal over a long-range to control homeostasis of distant tissues. In Aim 1 we propose to define the factors influencing luminal sensing by enteroendocrine cells. In Aim 2 we propose to characterize the mechanism(s) by which enteroendocrine cells signal peripheral tissues. These questions are currently difficult to address in mammals, as the tools for conditionally manipulating both endocrine cell subtypes and peripheral target tissues with single cell resolution have not yet been established. Thus, we propose to use Drosophila as a model to dissect mechanisms controlling the endocrine system.